Exposure of clinical MRSA heterogeneous strains to β-lactams redirects metabolism to optimize energy production through the TCA cycle.
Exposure of clinical MRSA heterogeneous strains to β-lactams redirects metabolism to optimize energy production through the TCA cycle.
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DOI：
10.1371/journal.pone.0071025
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rosato AE
中科院分区：
文献类型：
--
作者：
Keaton MA;Rosato RR;Plata KB;Singh CR;Rosato AE
耐甲氧西林金黄色葡萄球菌(MRSA)已成为医疗卫生和社区感染中最重要的病原体之一。甲氧西林耐药的先决条件是mecA，它编码一种对β-内酰胺类不敏感的青霉素结合蛋白PBP2a。来自医院和社区相关感染的耐甲氧西林金黄色葡萄球菌的一个特征是对β-内酰胺(HER)的异质性表达，其中只有一小部分(≤0.1%)的人群对苯唑西林(≥)10微克/毫升表现耐药，而在其他分离株中，大多数人群对高水平(同型耐药)表现出耐药。与异质性表达相关的机制既需要mecA的表达增加，也需要涉及β-内酰胺介导的SOS反应的突变事件以及相关的lexA和recA基因。在本研究中，我们采用基因芯片分析和整体生化图谱相结合的方法，结合气相色谱/质谱仪(GC/MS)和液质联用(LC/MS)，研究了HER-MRSA菌株在β-内酰胺介导的亚抑制浓度HER/HoR选择过程中的细胞生理学，以研究临床相关的异质性耐甲氧西林金黄色葡萄球菌中β-内酰胺类药物介导的HER/HoR选择过程中代谢途径和代谢组的变化。我们发现，与相应的SA13011-HER亲本菌株相比，苯唑西林选择的SA13011-HoR衍生物具有独特的特征，包括三羧基柠檬酸(TCA)循环中间产物的显著增加和发酵途径的减少。在SA13011-HER菌株中，Tca循环酶顺式乌头酸酶基因的失活取消了β-内酰胺介导的HER/HoR选择，表明了Tca循环活性改变在HER/HoR选择中的意义。这些结果提供了HER-MRSA临床菌株在暴露于β-内酰胺压力下所经历的代谢成本和适应的证据，表明能量产生被重新引导到供应细胞壁合成/代谢，这反过来又有助于在存在β-内酰胺抗生素的情况下的生存反应。
Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the most important pathogens both in health care and community-onset infections. The prerequisite for methicillin resistance is mecA, which encodes a β-lactam-insensitive penicillin binding protein PBP2a. A characteristic of MRSA strains from hospital and community associated infections is their heterogeneous expression of resistance to β-lactam (HeR) in which only a small portion (≤0.1%) of the population expresses resistance to oxacillin (OXA) ≥10 µg/ml, while in other isolates, most of the population expresses resistance to a high level (homotypic resistance, HoR). The mechanism associated with heterogeneous expression requires both increase expression of mecA and a mutational event that involved the triggering of a β-lactam-mediated SOS response and related lexA and recA genes. In the present study we investigated the cellular physiology of HeR-MRSA strains during the process of β-lactam-mediated HeR/HoR selection at sub-inhibitory concentrations by using a combinatorial approach of microarray analyses and global biochemical profiling employing gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) to investigate changes in metabolic pathways and the metabolome associated with β-lactam-mediated HeR/HoR selection in clinically relevant heterogeneous MRSA. We found unique features present in the oxacillin-selected SA13011-HoR derivative when compared to the corresponding SA13011-HeR parental strain that included significant increases in tricarboxyl citric acid (TCA) cycle intermediates and a concomitant decrease in fermentative pathways. Inactivation of the TCA cycle enzyme cis-aconitase gene in the SA13011-HeR strain abolished β-lactam-mediated HeR/HoR selection demonstrating the significance of altered TCA cycle activity during the HeR/HoR selection. These results provide evidence of both the metabolic cost and the adaptation that HeR-MRSA clinical strains undergo when exposed to β-lactam pressure, indicating that the energy production is redirected to supply the cell wall synthesis/metabolism, which in turn contributes to the survival response in the presence of β-lactam antibiotics.
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影响因子：
4.3
作者：
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